Pre-ART immune senescence predicts poor CD4+ T-cell recovery in PLWHIV on antiretroviral therapy
Background
For people living with human immunodeficiency virus (PLWHIV), a critical challenge remains immune reconstitution failure (IRF), characterized by suboptimal CD4+ T-cell recovery despite effective antiretroviral therapy (ART). This persistent immune deficit increases susceptibility to opportunistic infections and non-AIDS comorbidities. While ART effectively suppresses viral load, the underlying mechanisms preventing full immune recovery in some individuals are not fully understood, particularly the contribution of immune senescence to this failure. Understanding this gap could lead to more personalized therapeutic strategies.
Study Design
Researchers conducted a prospective cohort study involving 510 ART-initiating PLWHIV, assessing them at baseline (pre-ART) and after 48 weeks of treatment. Immune reconstitution (IR) was strictly defined as a CD4+ T-cell count increase exceeding 350 cells/uL. Initially, SenMayo gene set score analysis was performed on publicly available CD4+ T-cell scRNA-seq data. Subsequently, logistic regression was used to identify factors associated with non-immune reconstitution (NIR). Immunophenotyping, cytokine profiling (including TNF-α, IFN-γ, and CD-107a), and cellular senescence marker assessments (including p16, p21, p53, and senescence-associated β-galactosidase) were performed to characterize immune profiles.
Results
Bioinformatics analysis of ART-naïve CD4+ T-cell subtypes revealed elevated cellular senescence scores. In the prospective cohort, patients achieving IR were significantly younger than those with NIR (both in AIDS and non-AIDS subcohorts, p < 0.05). Multivariable analysis confirmed that age was an independent risk factor for NIR. Before ART initiation, the NIR group exhibited a distinctly senescent immune profile. This was characterized by a significant reduction in naïve T cells and an increase in terminally differentiated T cells. Furthermore, this group showed heightened chronic inflammation with elevated cytokine secretion. ART failed to fully reverse these immune abnormalities in the NIR group.
Cellular senescence was most pronounced in
CD4+ T cellswithin the NIR group prior to treatment, suggesting a pre-existing vulnerability.
Key Findings
- ART-naïve CD4+ T-cell subtypes showed elevated cellular senescence scores via bioinformatics analysis.
- Patients achieving immune reconstitution were significantly younger than non-reconstituters (p < 0.05).
- Age was identified as an independent risk factor for non-immune reconstitution.
- Non-immune reconstituters had reduced naïve T cells, increased terminally differentiated T cells, and heightened chronic inflammation pre-ART.
- Cellular senescence was most pronounced in CD4+ T cells of non-immune reconstituters before treatment.
Why It Matters
Considering immunological age and pre-ART immune senescent status could personalize antiretroviral therapy strategies for people living with HIV. This study highlights that a patient's immune profile before starting ART is a critical determinant of long-term CD4+ T-cell recovery. Integrating immune senescence markers into pre-ART assessments could identify individuals at higher risk for non-immune reconstitution, allowing for targeted interventions or adjunctive therapies. While this is an observational study, it paves the way for future research into senolytic or immunomodulatory agents that could reverse or mitigate pre-existing immune senescence, potentially improving immune outcomes beyond viral suppression alone. This could lead to more robust immune health and reduced long-term complications for PLWHIV.
hiv
immune-reconstitution
immune-senescence
cd4-t-cells
antiretroviral-therapy
cohort-study